CHRNA5/A3/B4 variant rs3743078 and nicotine-related phenotypes: Indirect effects through nicotine craving

Dvora Shmulewitz, Jacquelyn L. Meyers, Melanie M. Wall, Efrat Aharonovich, Amos Frisch, Baruch Spivak, Abraham Weizman, Howard J. Edenberg, Joel Gelernter, Deborah S. Hasin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Objective: Nicotine craving is considered an important element in the persistence of cigarette smoking, but little is known about the role of craving in the widely recognized association between variants mapped to the neuronal nicotinic acetylcholine receptor (CHRN) genes on chromosome 15 and nicotine phenotypes. Method: The associations between CHRNA5–CHRNA3–CHRNB4 variants and cigarettes per day (CPD), the Fagerström Test for Nicotine Dependence (FTND), and craving were analyzed in data from 662 lifetime smokers from an Israeli adult Jewish household sample. Indirect effects of genotype on nicotine phenotypes through craving were formally tested using regression and bootstrapping procedures. Results: At CHRNA3, allele G of rs3743078 was associated with increased craving, CPD, and FTND scores: Participants with one or two copies of the G allele had, on average, higher scores on the craving scale (p =.0025), more cigarettes smoked (p =.0057), and higher scores on the FTND (p =.0024). With craving in the model, variant rs3743078 showed a significant indirect effect through craving on CPD (p =.0026) and on FTND score (p =.0024). A sizeable proportion of the total rs3743078 effect on CPD (56.4%) and FTND (65.2%) was indirect through craving. Conclusions: These results suggest that nicotine craving may play a central role in nicotine use disorders and may have utility as a therapeutic target.

Original languageEnglish
Pages (from-to)227-237
Number of pages11
JournalJournal of Studies on Alcohol and Drugs
Issue number2
StatePublished - Mar 2016


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